title: Centrosomal Che-1 protein is involved in the regulation of mitosis and DNA damage response by mediating pericentrin (PCNT)-dependent Chk1 protein localization.
abstract: To combat threats posed by DNA damage, cells have evolved mechanisms, collectively termed DNA damage response (DDR). These mechanisms detect DNA lesions, signal their presence, and promote their repair. Centrosomes integrate G2/M checkpoint control and repair signals in response to genotoxic stress, acting as an efficient control mechanism when G2/M checkpoint function fails and mitosis begins in the presence of damaged DNA. Che-1 is an RNA polymerase II-binding protein involved in the regulation of gene transcription, induction of cell proliferation, and DDR. Here we provide evidence that in addition to its nuclear localization, Che-1 localizes at interphase centrosomes, where it accumulates following DNA damage or spindle poisons. We show that Che-1 depletion generates supernumerary centrosomes, multinucleated cells, and multipolar spindle formation. Notably, Che-1 depletion abolishes the ability of Chk1 to bind pericentrin and to localize at centrosomes, which, in its turn, deregulates the activation of centrosomal cyclin B-Cdk1 and advances entry into mitosis. Our results reinforce the notion that Che-1 plays an important role in DDR and that its contribution seems to be relevant for the spindle assembly checkpoint.
authors.affiliation: Laboratory of Epigenetics, Molecular Medicine Area, Regina Elena Cancer Institute, Via E. Chianesi 53, 00144 Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sorino
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bruno
authors.forename: Agata
authors.initials: A
authors.lastname: Desantis
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Di Certo
authors.forename: Simona
authors.initials: S
authors.lastname: Iezzi
authors.forename: Francesca
authors.initials: F
authors.lastname: De Nicola
authors.forename: Valeria
authors.initials: V
authors.lastname: Catena
authors.forename: Aristide
authors.initials: A
authors.lastname: Floridi
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
authors.forename: Claudio
authors.initials: C
authors.lastname: Passananti
authors.forename: Enrico
authors.initials: E
authors.lastname: Cundari
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fanciulli
mesh_terms: D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints / Q000502:physiology; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology; D008938:Mitosis / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C402637:AATF protein, human; D000941:Antigens; D051017:Apoptosis Regulatory Proteins; D019926:Cyclin B; D012097:Repressor Proteins; C086178:pericentrin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase
keywords: Centrosome; Che-1; Checkpoint Control; Chk1; DNA Damage Response; Mitosis; Mitotic Spindle; PCNT